C–H-Functionalization logic guides the synthesis of a carbacyclopamine analog

Abstract

SummaryThe chemical synthesis of carbacyclopamine analog 2, a cyclopamine analog with an all-carbon E-ring, is reported. The use of C–H-functionalization logic and further metal-catalyzed transformations allows for a concise entry to this new class of acid-stable cyclopamine analogs.

Decoding the Mechanism of Intramolecular Cu-Directed Hydroxylation of sp3 C–H Bonds

“…This has subsequently been exploited in several impressive syntheses. 19–21 As part of a natural product synthesis effort, the Baran group reinvestigated this interesting oxidation after a vast exploration of alternative methods and strategies failed. The reaction conditions were subsequently improved (ascorbic acid as reductant, shorter reaction times, and higher yields) and applied to the first synthesis of highly oxygenated polyoxypregnane steroids with useful biological properties.…”

“… − Derivatization of the C17 ketone of steroid substrates to generate a bidentate imino-pyridine ligand combined with the addition of a Cu I source (or Cu II + reductant) and dioxygen led to the selective hydroxylation of C12 with modest yields (up to 50%). This has subsequently been exploited in several impressive syntheses. − As part of a natural product synthesis effort, the Baran group reinvestigated this interesting oxidation after a vast exploration of alternative methods and strategies failed. The reaction conditions were subsequently improved (ascorbic acid as reductant, shorter reaction times, and higher yields) and applied to the first synthesis of highly oxygenated polyoxypregnane steroids with useful biological properties .…”

Synthesis of C-Nor-D-homo-steroidal Alkaloids and Their Derivatives

“…During this work the problem of reversing the endo/exo selectivity of the Wagner-Meerwein rearrangement was addressed effectively via applying Comins' reagent (20) and excess DMAP and using toluene as the solvent. 15 In fact the reaction course was shifted in favor of the desired endocyclic isomer reaching to an almost quantitative yield with the impressive ratio of 3.3:1 (endo/exo isomer) instead of 3:7 in previous approaches (Scheme 5).…”

“…To overcome the acid lability of cyclopamine and to gain more insight into structure-activity relationships, cyclopamine analogue 29 was synthesized. 20 In this derivative the oxygen atom in ring E was replaced by a CH moiety. The retrosynthetic analysis is outlined in Scheme 9.…”

De Novo Synthesis of the DEF-Ring Stereotriad Core of the Veratrum Alkaloids

“…Through utilization of a late-stage functionalization of cyclopamine, a kilogram-scale approach to the synthesis of saridegib has been developed . In addition to these exciting developments, it has been shown that introducing structural modifications to the parent structure of cyclopamine can allow increased stability as well as improved Hh signal inhibition . With these possibilities in mind, a de novo synthesis is attractive as it might allow modifications in different regions of the parent structure and potentially provide a more diverse array of analogues.…”